The present invention relates to a stable, lauryl alcohol containing formulation having superior skin penetration properties and improved antifungal properties for the topical application of an imidazole antifungal agent either by itself or in combination with a steroid anti-inflammatory agent. The produce is particularly suitable for treating fungal diseases such as tinea capitis, tinea corporis, tinea cruris, tinea pedis, tinea versicolor or cutaneous candidiasis.
A fungus is a very small microscopic type of plant cell which may grow on the skin and, under certain conditions, produce an infection. Such fungi-caused infections, the mycoses, are among the oldest known to man and have long been recognized as a highly prevalent health problem.
A variety of methods have been used for the treatment of fungal infections including the use of potassium iodide, Whitfield's ointment, undecylenic acid, antibiotics (e.g., nystatin and amphotericin B), griseofulvin and imidazole antifungal agents such as miconazole, clotrimazole, econazole and sulconazole. The imidazoles were the first broad-spectrum antifungals and are of considerable importance in clinical practice. Their broad spectrum of antifungal activity, extending to most pathogenic fungi, has provided an important advance in antifungal therapy.
Recently, it has been found that fungal infections can be effectively treated with a combination product containing corticosteroid anti-inflammatory agents and imidazole antifungal agents. Currently, the commercially available combination products using this concept are Lotrisone cream (clotrimazole 1%/betamethasone dipropionate 0.05%), Daktacort cream (miconazole nitrate 2%/hydrocortisone 1%) and Canesten HC cream (clotrimazole 1%/hydrocortisone 1%). Katz et al, Cutis 34, 183 (1984) and Wortzel, Cutis 30, 258 (1982) found that Lotrisone cream was therapeutically and mycologically better than clotrimazole 1% and betamethasone dipropionate 0.05% alone.
To be optimally effective, the imidazole antifungal agent and steroid anti-inflammatory agent must be brought into direct contact with the fungal infection being treated. Unfortunately, such infections are frequently located in hard-to-reach deeper skin layers, hyper-keratinized skin and/or nails. Hence, it would be desirable to have an imidazole antifungal agent, either by itself or in combination with a steroid anti-inflammatory agent, formulated in a vehicle having a high degree of skin penetration, enabling it to reach hard-to-reach fungal infections.
There is considerable literature on the use of permeation/penetration enhancers to increase the penetration of drug molecules into or through the skin. U.S. Pat. No. 4,775,678, Su et al, issued Oct. 4, 1988 discloses the use of a combination of petrolatum, a bodying agent such as cetyl alcohol, stearyl alcohol, cetearyl alcohol (a mixture of cetyl alcohol and stearyl alcohol) or stearic acid, and a solubility enhancer such as propylene glycol, hexylene glycol, or polyethylene glycol as a penetration enhancer for a clotrimazole-containing cream base.
U.S. Pat. No. 4,552,872, Cooper et al, issued Nov. 12, 1985 discloses the use of a diol and a cell-envelope disordering compound such as methyl laurate, oleic acid, and myristyl alcohol as a penetration enhancer for a corticosteroid.
Similarly, U.S. Pat. No. 4,537,776, Cooper et al, issued Aug. 27, 1985, discloses a penetration-enhancing vehicle for pharmaceutically-active agents consisting essentially of N-(2-hydroxyethyl)pyrrolidone and a cell-envelope disordering compound.
Cooper et al, J. Pharm. Sci. 74, 688-689 (1985) describe the use of oleic acid and oleyl alcohol as penetration enhancers for acyclovir.
Lauryl alcohol (1-dodecanol) has been found to be a skin penetration enhancer for several pharmaceutical agents.
Yamada et al in Chem. Pharm. Bull. vol. 35 (8), 3390-3398 (1987) disclose the effectiveness of lauryl alcohol as an absorption enhancer for molsidomine L (N-ethoxycarbonyl-3-morpholinosydononimine).
Aungst et al in Int. J. Pharm. 33, 225-234 (1986)disclose the effectiveness of lauryl alcohol and lauric acid as potent agents for increasing the skin penetration of naloxone.
Tsuzuki et al, Int. J. Pharm. 46, 19-23 (1988) disclose the effectiveness of lauryl alcohol as a penetration enhancer for indomethacin through shed snake skin.
U.S. Pat. No. 4,752,612, Saito, issued Jun. 21, 1988 discloses a method of percutaneously administering a non-steroid anti-inflammatory agent wherein the carrier system comprises a C.sub.10 -C.sub.26 aliphatic monoalcohol and a pyrrolidone-type solvent.
In Akazawa, Int. J. Pharm. 50 (1989) 53-60, lauryl alcohol was used with minoxidil and benzocaine in test formulations for evaluating an automated diffusion cell apparatus.
U.S. Pat. No. 4,299,826, Luedders, issued Nov. 10, 1981 discloses the use of lauryl alcohol as a penetration enhancer for erythromycin.
In Bhatt, Int. J. Pharm. 50 (1989) 197-203, lauryl alcohol was used with propylene glycol and acetaminophen in a test formulation for experiments directed towards developing a theoretical model for the transport of drugs across the stratum corneum.
British Pat. No. 1,518,683 (1978) discloses a skin permeation preparation comprising a pharmaceutically active agent at least partially dissolved in a carrier material mixture comprising at least one skin-compatible aliphatic C.sub.11 to C.sub.25 alcohol and one skin-compatible anionic and/or amphoteric tenside, such as a salt of a dialkanolamine or trialkanolamine.
In Mollgaard et al, Acta Pharm. Suec. 20 (1983) 443-450, it was found that the skin permeation of metronidazole, an imidazole, in propylene glycol was increased in vehicles containing C.sub.8, C.sub.10 or C.sub.12 alkanols. However, the same study showed that estradiol permeation was not increased by alkanols of chain length of less than 14 carbon atoms.
Lauryl alcohol is known to be a safe and acceptable ingredient for topical applications. Undiluted lauryl alcohol has been found to be practically non-irritating to the guinea pig. J. F. Treon, "Alcohols in Industrial Hygiene and Toxicology", 2nd ed, vol. II, F. A. Patty (Ed.), Interscience Publishers, New York (1963) p. 1468.
It is well known that the effectiveness of a penetration enhancer depends on the type of drug molecule and the composition of the formulation. Thus, in developing a topical formulation, the identification of an enhancer is only the first step, because reduction in penetration can occur as a multicomponent formulation is developed.
It is an objective of this invention to develop a product having superior skin penetration properties for both an imidazole antifungal agent alone and in combination with steroid anti-inflammatory agent.